Calcio, fósforo y Magnesio en Recién Nacido
Division
of Neonatology,
Cedars-Sinai Medical
Center, Los Angeles,
California.
Calcio:
Calcium
is the most abundant
mineral in the body.
By term gestation, the
average newborn has
accumulated between 20
and 30 grams of
elemental calcium, 80%
of which are accreted
during the third
trimester of
pregnancy.
Approximately 99% of
all calcium is located
in the skeleton; only
about one-third of
this is readily
exchangeable with the
extracellular fluid.
Serum calcium exists
in three separate
fractions which are in
dynamic equilibrium.
Protein-bound calcium
represents about 40%
of the total serum
concentration of
calcium, with albumin
representing the
primary binding
protein. Calcium is
also found complexed
to a number of anions,
such as citrate,
phosphate,
bicarbonate, and
sulfate. The complexed
calcium accounts for
about 10% of the total
calcium. Free ionized
calcium accounts for
the remainder of the
serum calcium, making
up about 50% of the
total value. It is
this form which
represents the
physiologically active
form of calcium.
The
serum concentration of
calcium varies
significantly during
the immediate neonatal
period. In general,
the serum calcium
concentration
decreases over the
first days of life,
followed by a gradual
increase to adult
concentrations by the
second or third week
of life.
Phosphorus
As
with calcium,
approximately 80% of
the phosphorus in the
term newborn is
accumulated during the
last trimester of
pregnancy. About 85%
of the total body
phosphorus is found in
the skeleton. The
plasma concentrations
of inorganic phosphate
in the neonatal period
are maintained at
concentrations greater
than those of the
adult. Phosphorus in
body fluids is divided
between an organic
fraction -- composed
of a number of
phospholipids and
phosphoesters -- and
inorganic phosphate.
Magnesium
(Mg) is the second
most common
intracellular cation
in the body. By term
gestation, the newborn
infant contains
approximately 20 mg of
Mg per 100 gm of
fat-free weight. Of
the body's total Mg
content, about 60% is
contained in the bone,
another 29% is found
in muscle, and the
remainder is
distributed through
the remaining soft
tissues. Approximately
1% of the total body
megnesium is located
in extracellular
space. The serum
concentrations of
magnesium are
maintained within
relatively tight
limits and are
essentially the same
for newborns, infants,
children, and adults
with a normal range of
1.5 to 2.8 mg/dl.
Regulation
of Serum Concentration
The
serum calcium
homeostasis is
maintained primarily
through the
interaction of three
hormones --
parathyroid hormone
(PTH), calcitonin
(CT), and vitamin D --
and their actions on
the gastrointestinal
tract, kidney, and
bone.
Under
normal conditions, a
decrease in the serum
ionized calcium
concentration
stimulates production
and secretion of PTH.
PTH, in turn, acts on
bone, stimulating
resorption, thereby
releasing calcium and
inorganic phosphate
into the extracellular
fluid and circulation.
PTH also acts on the
kidney to increase the
urinary excretion of
calcium. PTH
indirectly enhances
the ghastrointestinal
absorption of calcium
through its effects on
the metabolism of
vitamin D. The net
effect of PTH is to
increase the serum
concentration of
calcium.
Calcitonin
(CT) is produced by
the parafollicular
cells of the thyroid.
CT secretion is
stimulated when serum
concentrations of
calcium are elevated.
CT acts on bone to
inhibit osteocyte-and
osteoclast mediated
bone resorption. At
high doses, it also
acts on the kidney to
increase the urinary
excretion of both
calcium and inorganic
phosphate. The net
effect of CT is to
decrease the
concentration of
calcium and inorganic
phosphate.
Vitamin
D is either ingested
in the diet and
absorbed from the
gastrointestinal tract
or produced in skin
under the influence of
ultraviolet light.
Before it reaches its
final active form,
1,25-dihydroxyvitamin
D, vitamin D must
first undergo two
hydroxylation steps -
the first in the liver
and the second in the
proximal tubule of the
kidney. It is this
active metabolite of
vitamin D that acts on
small intestine to
stimulate the active
absorption of calcium.
It also acts on bone,
where in conjunction
with PTH, it
stimulates bone
resorption. The
production of 1,25
dihydroxyvitamin D by
the renal proximal
tubule is enhanced by
hypocalcemia,
hypophosphatemia, and
PTH. The net effect of
1,25-dihydroxy-vitamin
D is to increase the
serum concentration of
calcium.
There
are no hormones which
appear to respond
directly to variations
in the serum
concentration of
inorganic phosphate.
The serum
concentration of
inorganic phosphate
appears to be
primarily regulated
through the kidney by
means of the tubular
reabsorption of
inorganic phosphate.
There
are no proven hormones
that consistently
regulate the serum
concentration
of magnesium. There is
an inverse
relationship between
magnesium
concentration and PTH
secretion. At
supraphysiologic
concentration of
magnesium, the
secretion of PTH is
decreased, while at
very low magnesium
concentrations the
secretion is
increased.
Hypomagnesemia results
in suppression of PTH
activity even in the
face of significant
hypocalcemia. The
kidney appears to be
the primary site for
regulation of serum
magnesium
concentration.
Gastrointestinal
Transport
The
gastrointestinal tract
is the primary site
involved in the
long-term regulation
of calcium balance.
Absorption of calcium
by the small intestine
involves two separate
mechanisms. Passive
absorption occurs at
similar rates
throughout the entire
small intestine and is
linearly related to
the intraluminal
calcium concentration.
The passive absorption
of calcium does not
appear to be a
regulated process, in
that there are no
recognized hormones
that modify the rate
of transport via this
route.
Active
transport of calcium
in the intestine
contrasts markedly
with passive
absorption, in that it
occurs predominantly
in a relatively small
area of the small
intestine and is
strongly influenced by
vitamin D. Active
intestinal absorption
of calcium occurs
primarily in the
duodenum. Here
1,25-dihydroxyvitamin
D augments active
absorption of calcium.
The
actual mechanism
through which
1,25-dihydroxyvitamin
D enhances calcium
absorption remains to
be elucidated. The
activity of intestinal
alkaline phosphatase
is increased upon
exposure to
1,25-dihydroxyvitamin
D, as is the mucosal
concentration of a
calcium-binding
protein. The relative
importance of active
versus passive
intestinal absorption
of calcium in the
human neonate is
unknown.
In
preterm infants, as
calcium intake
increases, so does the
intestinal absorption
of calcium. Human milk
fed and formula fed
infants supplemented
with vitamin D
exhibited
significantly greater
absorption of calcium
compared with their
unsupplemented
counterparts.
Intestinal maturation
with regard to vitamin
D responsiveness is
accelerated by preterm
delivery. Although the
above does not
establish the relative
importance of passive
and active mechanisms
or the timing of
intestinal vitamin D
responsiveness with
regard to calcium
absorption, they do
indicate that
absorption of calcium
is not a limiting
issue for the preterm
infant. With proper
attention to dietary
manipulation, adequate
calcium balance should
be attained.
A
number of
carbohydrates and
glucose polymers
enhance the intestinal
absorption of calcium.
The precise mechanism
through which these
carbohydrates modify
intestinal calcium
absorption is unclear,
but it is known that
absorption occurs via
a process that is
independent of the
actions of vitamin D.
Osmotic forces that
enhance the net
intestinal absorption
of water also enhances
the passive absorption
of calcium.
Fractional
intestinal absorption
of calcium is enhanced
by dietary restriction
of calcium or
inorganic phosphate.
Under these conditions
there is increased
production of
1,25-dihydroxyvitamin
D with resultant
increase in active
intestinal absorption
of calcium.
Fat
malabsorption has the
potential to impair
intestinal calcium
absorption. Preterm
infants are not likely
to have an
intraluminal
concentration of bile
salts which is
sufficient for the
establishment of a
micelle-phase, leading
to reduced absorption
of fat. The unabsorbed
free fatty acids are
then available to
interact with ionic
calcium to form
insoluble soaps which
are not available for
absorption. Although
steatorrhea can be
significantly reduced
in preterm infants by
administering a
significant proportion
of dietary fat as
medium chain
triglycerides (MCT),
it is not clear that
this practice
significantly improves
intestinal calcium
absorption.
Significant amounts of
endogenous calcium are
lost daily through
intestinal secretion.
This portion of the
intraluminal calcium
is reabsorbed at a
level of efficiency
less than that of
dietary calcium.
Compared
to calcium, much less
is known about the
intestinal absorption
of inorganic
phosphate. The
absorption of
inorganic phosphate
occurs throughout the
entire small
intestine, but the
jejunum exhibits the
highest rate of
transport. Both active
and passive process
are involved in the
movement of inorganic
phosphate from the
intestinal mucosa to
the serosa.
The
regulation of
intestinal inorganic
phosphate appears to
be centered on
the cotransport
of sodium and
inorganic phosphate.
With restriction of
dietary inorganic
phosphate, fractional
intestinal absorption
of inorganic phosphate
increases. Dietary
inorganic phosphate
restriction increases
the production of
1,25-dihydroxyvitamin
D and thereby augments
the active component
of inorganic phosphate
absorption. There is
also an increase in
intestinal absorption
of inorganic phosphate
in response to dietary
restriction that is
independent of vitamin
D. The intestinal
absorption is enhanced
when the intraluminal
environment is
somewhat acidic. In
contrast, metabolic
acidosis, which should
decrease intracellular
pH, markedly decreases
inorganic phosphate
uptake.
In
preterm and term
infants inorganic
phosphate is well
absorbed from the
gastrointestinal tract
regardless of the type
of feeding given and
generally independent
of the intake of
vitamin D. The
percentage of
inorganic phosphate
absorbed increases as
inorganic phosphate
intake decreases, but
the absolute
absorption of
inorganic phosphate
increases
proportionally with
increasing intake. In
infants fed soy-based
formula, the
intestinal absorption
of inorganic phosphate
is lower than infants
fed cow's milk-base
formula. It appears
that by increasing the
calcium and inorganic
phosphate content of
soy formula, this
problem may be
overcome.
Minimal
information is
availble with regard
to the
gastrointestinal
handling of magnesium.
In adults, intestinal
absorption of
magnesium ranges
between 34% to 62% of
total intake. In
preterm infants
magnesium absorption
is
somewhat higher,
ranging from 50% to
80%.
The
primary site of
absorption of
magnesium is the small
intestine with similar
rates of transport for
jejunum and ileum.
Colonic absorption of
magnesium also occurs.
Intestinal magnesium
absorption decreases
with an increase in
dietary calcium.
Vitamin D has
also been observed to
augment intestinal
absorption of
magnesium. Glucose
polymers have been
observed to enhance
jejunal magnesium
absorption.
Significant amounts of
magnesium are secreted
into the intestinal
tract. Bile,
pancreatic juice, and
gastric juice all
contain large amounts
of magnesium. Almost
all of the secreted
magnesium is
reabsorbed, so that
under normal
conditions, secreted
magnesium accounts
only for a small
proportion of the
total fecal magnesium.
Renal
Regulation of Mineral
Homeostasis
The
kidney plays a very
important role in
calcium homeostasis.
The movement of
calcium from the
gastrointestinal tract
and bone may act as
the primary
determinant of the
serum calcium
concentration, but it
is the action of the
kidney that provides
the fine-tuning for
the whole system.
Many factors
have been identified
that influence renal
calcium excretion.
Primary among them is
PTH. Patients who are
hypoparathyroid
excrete more calcium
than those who are
hyperparathyroid.
Parenteral
administration of
various calcitonin
preparations have been
noted to increase
urinary calcium
excretion. The renal
effect of calcitonin
is short-lived.
In
the first few days of
life, urinary calcium
excretion has been
observed to be low in
both term and preterm
infants. Over the next
two to three weeks, a
steady increase in
urinary calcium
excretion is noted. In
term infants, calcium
excretion is simialr
to that observed in
older infants and
children. Preterm
infants in the first
few days of life will
increase their serum
calcium concentration
in response to
exogenous PTH.
However, only
equivocal changes in
urinary excretion of
calcium and inorganic
phosphate have been
noted in treated
preterm infants.
The
loop diuretics,
furosemide and
ethacrynic acid, are
recognized to increase
the urinary excretion
of calcium. These
agents act at the loop
of Henle to inhibit
the active
reabsorption of sodium
and chloride. Since
calcium reabsorption
in the ascending limb
of the loop of Henle
is dependent on the
active reabsorption of
these ions, calcium
reabsorption is
secondarily inhibited.
The resulting
hypercalciuria can
place the infant at
risk for development
of nephrocalcinosis,
and in VLBW infants,
can further impair an
already marginal
calcium balance.
Chronic administration
of thiazide diuretics,
which are often used
as an alternative to
loop diuretics, is
also known to increase
urinary excretion of
calcium.
The
kidney is the primary
regulator of the
plasma concentration
of inorganic
phosphate. As the
plasma concentration
of inorganic phosphate
increases, the amount
of inorganic phosphate
reabsorbed by the
tubule increases until
its maximal
reabsorptive capacity
is reached. Up to this
point, only very
minimal changes in
urinary inorganic
phosphate excretion
are
noted. Once this point
is reached, further
incremental increass
in plasma inorganic
phosphate
concentration lead to
a proportional
increase in urinary
excretion of inorganic
phosphate.
Administration of
exogenous PTH produces
a decrease in tubular
reabsorption of
inorganic phosphate.
Human growth hormone
decreases urinary
excretion of inorganic
phosphate and
increases the serum
inorganic phosphate
concentration.
Volume
expansion has been
found to increase the
urinary excretion of
inorganic phosphate.
Volume expansion
itself has been found
to cause a decrease in
plasma ionized calcium
concentration and a
increase in PTH
concentration. It's
thought that the
saline load introduced
with volume expansion
and the resultant
increase in sodium
excretion secondarily
inhibits inorganic
phosphate
reabsorption. A
reduction in inorganic
phosphate intake is
followed by a decrease
in the urinary
excretion of inorganic
phosphate. This is
independent of the
action of PTH.
Infants
fed human milk tend to
have a lower inorganic
phosphate intake than
their formula-fed
counterparts. The
plasma concentration
of inorganic phosphate
also is usually lower
in human milk fed than
in formula fed
infants.
It
is the kidney that is
the primary regulator
of extracellular
magnesium
concentration.
Parenteral
administration of PTH
has been shown to
increase the
reabsorption of
magnesium. PTH
administration causes
an increase in the
plasma concentration
of magnesium but a
decrease in urinary
excretion of
magnesium. Ingestion
of a
magnesium-deficient
diet leads to a marked
reduction in urinary
excretion of
magnesium.
Urinary
excretion of magnesium
is low in the
immediate neonatal
period. There is no
clear relationship
between dietary intake
in infancy and urinary
excretion of
magnesium. Urinary
excretion of magnesium
is higher in
human-milk fed term
infants compared to
infants fed with
either human milk with
a phosphate supplement
or a cow's milk based
formula.
Metabolismo del hueso y de la vitamina D
Las tasas de formación ósea están coordinadas con las modificaciones del metabolismo mineral tanto en el intestino como en el riñón. La ingesta dietética o la absorción intestinal inadecuadas de calcio producen una disminución del calcio sérico y de su fracción ionizada. Esto sirve como señal para la síntesis de secreción de PTH, lo que ocasiona una mayor resorción ósea para elevar el calcio sérico, un aumento de la reabsorción tubular distal de calcio y mayores tasas de síntesis renal de 1,25-dihidroxí vitamina D (1,25[OH]2D] o calcitriol), el metabilito más activo de la vitamina D (Fig. 647-1). Por lo tanto, la homeostasis del calcio está controlada por el intestino, ya que la disponibilidad de l,25(OH)2D será la que determine finalmente la fracción de calcio ingerido que se absorbe.
Por el contrario, la homeostasis del fósforo está regulada por el riñón, ya que la absorción intestinal de fosfato es casi completa y es la excreción renal la que determina el nivel sérico. Una absorción intestinal excesiva de fosfato produce una disminución del calcio sérico ionizado y una elevación de la secreción de PTR, lo que ocasiona fosfaturia, por lo que se disminuye el fosfato sérico y se permite la elevación del calcio. La hipofosfatemia bloquea la secreción de PTH y favorece la síntesis renal de 1,25(OH)2D. Este último compuesto también favorece una mayor absorción intestintal de fosfato.
Para estudiar el raquitismo es necesario conocer el metabolismo de la vitamina D (véase la Fig. 647-1). La piel contiene 7-dehidrocolesterol, que se convierte en vitamina D3 por la radiación ultravioleta; también se producen otros esteroles inactivos de la vitamina D.
La exposición escasa de la piel a la luz ultravioleta (debida a las nubes o a las ropas) ocasiona raquitismo (véanse los Capítulos 43.6 y 43.7). La vitamina D es transportada a continuación por el torrente sanguíneo hasta el hígado por medio de una proteina de unión de la vitamina D (PUD), que transporta todas las formas de vitamina D. La concentración plasmática de vitamina D libre o no unida es mucho menor que la de los metabolitos de vitamina D unidos a la proteína de unión. La vitamina D también puede entrar en la vía metabólica por ingestión en la dieta de vitamina D2 (ergocalciferol) o D3 (colecalciferol), o ambas, absorbidas en el intestino junto con otras vitaminas liposolubles por la acción de las sales biliares. Después de la absorción, la vitamina D ingerida es transportada por los quilomicrones hasta el hígado donde, junto con la vitamina D3, es convertida en 25-hidroxi vitamina D (25[OH]D) por la acción de una enzíma microsomal hepática que requiere oxígeno, NADPH y Magnesio para hidroxilar la vitamina D en el átomo de carbono de la posición 25. La 25(OH)D es transportada a continuación por la proteína de unión hasta el riñón, donde experimenta una nueva metabolización. La 25(OH)D es el principal metabolito circulante de vitamina D en los seres humanos, con una concentración de 20-80 ng/mL (Cuadro 647-1). Dado que su síntesis está regulada débilmente por un mecanismo de retroacción, sus niveles píasmáticos se elevan en el verano y descienden en el invierno. La ingesta elevada de vitamina D hace elevarse los niveles plasmáticos de 25(OH)D hasta muchas veces sus valores normales, pero la propia vitamina D original es absorbida por el tejido adiposo.
Valores
de los metabolitos de
la vitamina D
en el plasma de
sujetos normales sanos
Metabolito
Valor plasmático
Vitamina D2 1-2 ng/mL
Vitamina D3 1 -2 ng/mL
25(OH)D2 4-10 ng/mL
25(OH)D3 12-40 ng/mL
25(OH)D total 15-50 ng/mL
24,25(OH)2D 1-4 ng/mL
1,25(OH)2D
Lactancia 70-100 ng/mL
Infancia 30-50 ng/mL
Adolescencia 40-80 ng/mL
Edad adulta 20-35 ng/mL
Vía
metabólica de la
vitamina D, en la que
se indica su conversión
en la hormona 1,25(OH)2D3
y en
24,25(OH>2D3.
La vitamina D2 (ergosterol),
de origen vegetal,
parece seguir pasos
metabólicos
similares.
Vitamina D2 o D3 de
7-Dehidrocolesterol en la piel
¯
Radiación ultravioleta (288 nm) origen dietético
¯ ¯ Vitamina D3
¯
25-hidroxilasa microsomal hepática
¯
¾¾¾¾¾ 25(OH)D3 ¾¾® Producto de degradación
½ 25 (OH)D-26,23-lactona
½
1alfa-hidroxilasa ½ ½
mitocondrial renal ½ hidroxilasa renal ½
¯ ¯
Ca2+ sérico bajo Ca2+ sérico elevado
Fosfato bajo
Hormona paratiroidea ½
¯ ¯
1,25(OH)2D3
24,25(OH>2D3
® Favorece la disolución ® ¿Función biológica?
y la mineralización óseas ® ¿Inactiva?
® Favorece la absorción ® ¿Importante en la mineralización?
intestinal de calcio y de fosfato
® El producto de degradación
es el ácido calcitroico
En el riñón, la 25(OH)D sufre una nueva hidroxilación, dependiendo de la concentración sérica existente de calcio, fosfato y PTH. Si el calcio o el fosfato están reducidos a la PTH elevada, se activa la enzima 25(OH)D-1alfa-hidroxilasa y se forma 1,25(OH)2D (véase la Fig. 647-1). Este metabolito circula a una concentración que tan sólo supone el 0.1 % del nivel de 25(OH)D (véase el Cuadro 647-1) y actúa sobre el intestino para aumentar el transporte activo de calcio y estimular la absorción de fosfato.
Dado que la 1~-hidroxi-lasa es una enzima mitocondrial sometida a una estrecha regulación por retroacción, la síntesis de 1,25(OH)2D disminuye una vez normalizados los valores séricos de calcio y de fosfato. La 1,25(OH)2D excesiva es convertida en un metabolito inactivo. En presencia de unas concentraciones normales o elevadas de calcio o de fosfato séricos, se activa la 25(OH)D-24-hidroxilasa renal, produciendo 24,25-dihí-droxi vitamina D (24,25[OH]2D), que es una vía para la eliminación del exceso de vitamina D, ya que los niveles séricos de 24,25(OR)2D (1-5 ng/mL) se elevan después de la ingestión de grandes cantidades de vitamina D. Aunque después de la administración oral puede haber hipervitaminosis D y producción de metabolitos inactivos (véase el Capítulo 43.7), la exposición intensa de la piel a la luz solar no suele producir niveles tóxicos de 25 (OH)D3, lo que sugiere la existencia de una regulación natural de la producción de este metabolito en el tejido cutáneo.
Los valores séricos de 1,25 (OH)2D son más elevados en los niños que en los adultos, no están sujetos a variaciones estacionales y alcanzan su máximo en el primer año de vida y de nuevo durante el «estirón» de la adolescencia. Estos valores se deben interpretar teniendo en cuenta las concentraciones de calcio, fosfato y PTH en suero, y también en relación con el perfil completo de metabolitos de la vitamina D.
El déficit de minerales impide el proceso normal de mineralización ósea. Si existe déficit mineral en el cartílago epifisario, el crecimiento se lentifica y la edad ósea se retrasa; es el proceso denominado raquitismo. La mala mineralización del hueso trabecular, que da lugar a una mayor proporción de osteoide no mineralizado, constituye la osteomalacia. El raquitismo tan sólo se encuentra en los niños en crecimiento antes de la fusión de las epífisis, mientras que la osteomalacia está presente en todas las edades. Todos los pacientes con raquitismo padecen osteo malacia, pero no todos los pacientes con osteomalacia padecen raquitismo. No se deben confundir estos procesos con la osteoporosis, situación en la que existe igual pérdida de volumen óseo y mineral, causada en la infancia por la administración de g1ucocorticoides, presente en 1os sindromes de Turner y Klinefelter, o como afección idiopática.
El raquitismo se puede clasificar como debido a déficit de calcio o a déficit de fosfato. Dado que el mineral óseo está compuesto por ambos iones, la insuficiencia de cualquiera de ellos en el líquido extracelular que baña la superficie de mineralización del hueso da lugar a raquitismo y osteomalacia. Los dos tipos de raquitismo se diferencian por sus manifestaciones clínicas .